Alleviated T cell exhaustion and SLC1A3-mediated stroma-remodelling dictate chemoimmunotherapy efficacy in oesophageal squamous cell carcinoma.

Abstract

Combining chemotherapy with anti-programmed cell death protein-1 (PD-1) improves clinical outcomes in oesophageal squamous cell carcinoma (ESCC), yet the underlying synergistic mechanism remains obscured. Moreover, 30-50% of patients still derive no therapeutic benefit from the combination strategy, highlighting the need to decipher and overcome resistance. We sought to investigate the mechanisms by which chemotherapy augments the responses to immune checkpoint blockade and elucidate the factors contributing to persistent resistance in non-responding patients. We designed a systematic investigation involving longitudinal sampling of ESCC tissues both from patients treated with chemotherapy plus anti-PD-1 and anti-PD-1 monotherapy. The tumour microenvironment (TME) was then comprehensively characterised using single-cell transcriptomics, T cell receptor repertoire analysis, multiplex immunohistochemistry and murine models. We demonstrated that combination therapy exerted superior antitumour efficacy by mitigating immune checkpoint engagements (TIGIT-NECTIN2 and NECTIN1-CD96) between epithelial-stress tumour cells and CD8⁺ T cells, thereby preventing T cells from exhaustion and boosting vitality. In non-responders, we identified a subset of tumour cells with high SLC1A3 expression, which localised at the tumour boundary and interacted with COL1A1⁺ myofibroblastic cancer-associated fibroblasts, inducing an extracellular matrix-enriched TME that hindered the infiltration of CD8⁺ T cells. Inhibiting SLC1A3 significantly enhanced the efficacy of chemotherapy plus anti-PD-1, underscoring its potential as a therapeutic target. This study elucidates the synergistic mechanisms and identifies key resistance pathways underlying chemo-immunotherapy combinations in patients with ESCC, providing a scientific basis for refining future combination therapeutic regimens.